EP2877467B1 - 2-(azaindol-2-yl)benzimidazoles as pad4 inhibitors - Google Patents
2-(azaindol-2-yl)benzimidazoles as pad4 inhibitors Download PDFInfo
- Publication number
- EP2877467B1 EP2877467B1 EP12740581.9A EP12740581A EP2877467B1 EP 2877467 B1 EP2877467 B1 EP 2877467B1 EP 12740581 A EP12740581 A EP 12740581A EP 2877467 B1 EP2877467 B1 EP 2877467B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pyrrolo
- pyridin
- methyl
- benzo
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003112 inhibitor Substances 0.000 title description 15
- VEZJRJGLFIXQHG-UHFFFAOYSA-N 2-(1h-benzimidazol-2-yl)-1h-benzimidazole Chemical class C1=CC=C2NC(C=3NC4=CC=CC=C4N=3)=NC2=C1 VEZJRJGLFIXQHG-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 301
- 150000003839 salts Chemical class 0.000 claims description 126
- 229910052739 hydrogen Inorganic materials 0.000 claims description 104
- 239000001257 hydrogen Substances 0.000 claims description 65
- -1 (3S,4R)-3-amino-4-hydroxypiperidin-1-yl Chemical group 0.000 claims description 45
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 41
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 37
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 22
- 206010025135 lupus erythematosus Diseases 0.000 claims description 20
- 206010047115 Vasculitis Diseases 0.000 claims description 16
- 201000004681 Psoriasis Diseases 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 11
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 11
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 11
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 10
- 208000006673 asthma Diseases 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 8
- KNMCDXAIVNPMQX-LJQANCHMSA-N [(3r)-3-aminopiperidin-1-yl]-[2-[1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methylbenzimidazol-5-yl]methanone Chemical compound CN1C=2C(OC)=CC(C(=O)N3C[C@H](N)CCC3)=CC=2N=C1C1=CC2=CC=CN=C2N1CC1CC1 KNMCDXAIVNPMQX-LJQANCHMSA-N 0.000 claims description 6
- PYUZHTRYLVLMAP-QGZVFWFLSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethylpyrrolo[2,3-b]pyridin-2-yl)-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC=CN=C2N(CC)C=1C(N(C1=CC=2)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 PYUZHTRYLVLMAP-QGZVFWFLSA-N 0.000 claims description 5
- JCCVZBCVMBEDEN-QGZVFWFLSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethylpyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC=CN=C2N(CC)C=1C(N(C1=C(OC)C=2)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 JCCVZBCVMBEDEN-QGZVFWFLSA-N 0.000 claims description 5
- PZGSGOGBUMTSJY-LJQANCHMSA-N [(3r)-3-aminopiperidin-1-yl]-[2-[1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-2-yl]-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C=C2N(C)C(C=3N(C4=NC=CC=C4C=3)CC3CC3)=NC2=CC=1C(=O)N1CCC[C@@H](N)C1 PZGSGOGBUMTSJY-LJQANCHMSA-N 0.000 claims description 5
- LGMQWHDIEKFXIE-PGRDOPGGSA-N [(3s,4r)-3-amino-4-hydroxypiperidin-1-yl]-[2-[1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-2-yl]-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C=C2N(C)C(C=3N(C4=NC=CC=C4C=3)CC3CC3)=NC2=CC=1C(=O)N1CC[C@@H](O)[C@@H](N)C1 LGMQWHDIEKFXIE-PGRDOPGGSA-N 0.000 claims description 5
- DFMWXZVRHCUIDX-MRXNPFEDSA-N [(3r)-3-aminopiperidin-1-yl]-[1-methyl-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-2-yl]benzimidazol-5-yl]methanone Chemical compound C=1C=C2N(C)C(C=3N(C4=NC=CC=C4C=3)CC(F)(F)F)=NC2=CC=1C(=O)N1CCC[C@@H](N)C1 DFMWXZVRHCUIDX-MRXNPFEDSA-N 0.000 claims description 4
- CUZDPEBQVSHMAS-QGZVFWFLSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethyl-5-methoxypyrrolo[2,3-b]pyridin-2-yl)-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC(OC)=CN=C2N(CC)C=1C(N(C1=CC=2)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 CUZDPEBQVSHMAS-QGZVFWFLSA-N 0.000 claims description 4
- LMJKAUYYQOXVBH-HXUWFJFHSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethylpyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-(2-methylpropyl)benzimidazol-5-yl]methanone Chemical compound C=1C2=CC=CN=C2N(CC)C=1C(N(C1=C(OC)C=2)CC(C)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 LMJKAUYYQOXVBH-HXUWFJFHSA-N 0.000 claims description 4
- NGVGPCGPMJWOCO-MRXNPFEDSA-N [(3r)-3-aminopiperidin-1-yl]-[7-methoxy-1-methyl-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-2-yl]benzimidazol-5-yl]methanone Chemical compound C=1C=2N=C(C=3N(C4=NC=CC=C4C=3)CC(F)(F)F)N(C)C=2C(OC)=CC=1C(=O)N1CCC[C@@H](N)C1 NGVGPCGPMJWOCO-MRXNPFEDSA-N 0.000 claims description 4
- VXZHYWCKALGSDQ-LJQANCHMSA-N [(3r)-3-aminopiperidin-1-yl]-[7-methoxy-1-methyl-2-[1-(2-methylpropyl)pyrrolo[2,3-b]pyridin-2-yl]benzimidazol-5-yl]methanone Chemical compound C=1C=2N=C(C=3N(C4=NC=CC=C4C=3)CC(C)C)N(C)C=2C(OC)=CC=1C(=O)N1CCC[C@@H](N)C1 VXZHYWCKALGSDQ-LJQANCHMSA-N 0.000 claims description 4
- JCCVZBCVMBEDEN-KRWDZBQOSA-N [(3s)-3-aminopiperidin-1-yl]-[2-(1-ethylpyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC=CN=C2N(CC)C=1C(N(C1=C(OC)C=2)C)=NC1=CC=2C(=O)N1CCC[C@H](N)C1 JCCVZBCVMBEDEN-KRWDZBQOSA-N 0.000 claims description 4
- PYUZHTRYLVLMAP-UHFFFAOYSA-N (3-aminopiperidin-1-yl)-[2-(1-ethylpyrrolo[2,3-b]pyridin-2-yl)-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC=CN=C2N(CC)C=1C(N(C1=CC=2)C)=NC1=CC=2C(=O)N1CCCC(N)C1 PYUZHTRYLVLMAP-UHFFFAOYSA-N 0.000 claims description 3
- YEKXWBBPTLBIFX-UHFFFAOYSA-N (3-aminopiperidin-1-yl)-[2-(1-ethylpyrrolo[3,2-c]pyridin-2-yl)-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CN=CC=C2N(CC)C=1C(N(C1=CC=2)C)=NC1=CC=2C(=O)N1CCCC(N)C1 YEKXWBBPTLBIFX-UHFFFAOYSA-N 0.000 claims description 3
- QWCHTDZPCMJADP-MRXNPFEDSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethyl-5-hydroxypyrrolo[2,3-b]pyridin-2-yl)-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC(O)=CN=C2N(CC)C=1C(N(C1=CC=2)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 QWCHTDZPCMJADP-MRXNPFEDSA-N 0.000 claims description 3
- MKKDRCQQVXGTHG-QGZVFWFLSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethyl-5-methoxypyrrolo[2,3-c]pyridin-2-yl)-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC(OC)=NC=C2N(CC)C=1C(N(C1=CC=2)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 MKKDRCQQVXGTHG-QGZVFWFLSA-N 0.000 claims description 3
- XMKOCOWOTAXPIB-MRXNPFEDSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethylpyrrolo[2,3-b]pyridin-2-yl)-1-methyl-7-(trifluoromethoxy)benzimidazol-5-yl]methanone Chemical compound C=1C2=CC=CN=C2N(CC)C=1C(N(C1=C(OC(F)(F)F)C=2)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 XMKOCOWOTAXPIB-MRXNPFEDSA-N 0.000 claims description 3
- PXEKOCDKODNCAO-QGZVFWFLSA-N [(3r)-3-aminopiperidin-1-yl]-[2-(1-ethylpyrrolo[2,3-c]pyridin-2-yl)-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C2=CC=NC=C2N(CC)C=1C(N(C1=CC=2)C)=NC1=CC=2C(=O)N1CCC[C@@H](N)C1 PXEKOCDKODNCAO-QGZVFWFLSA-N 0.000 claims description 3
- FQGRLSQSAFNRCE-LJQANCHMSA-N [(3r)-3-aminopiperidin-1-yl]-[7-methoxy-2-[1-(2-methoxy-2-methylpropyl)pyrrolo[2,3-b]pyridin-2-yl]-1-methylbenzimidazol-5-yl]methanone Chemical compound C=1C=2N=C(C=3N(C4=NC=CC=C4C=3)CC(C)(C)OC)N(C)C=2C(OC)=CC=1C(=O)N1CCC[C@@H](N)C1 FQGRLSQSAFNRCE-LJQANCHMSA-N 0.000 claims description 3
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 399
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 231
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
Definitions
- the present invention is directed to certain novel compounds, in accordance with claim 1, which are inhibitors of PAD4, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment of various disorders.
- Compounds which inhibit PAD4 may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.
- PAD4 is a member of the peptidylarginine deiminase (PAD) family of enzymes capable of catalysing the citrullination of arginine into citrulline within peptide sequences. PAD4 is responsible for the deimination or citrullination of a variety of proteins in vitro and in vivo, with consequences of diverse functional responses in a variety of diseases ( Jones J.E. et al, Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627 ).
- exemplar diseases include rheumatoid arthritis, diseases with neutrophilic contributions to pathogenesis (for example vasculitis, systemic lupus erythematosus, ulcerative colitis) in addition to oncology indications.
- PAD4 inhibitors may also have wider applicability as tools and therapeutics for human disease through epigenetic mechanisms.
- RA Rheumatoid Arthritis
- RA is an autoimmune disease affecting approximately 1% of the population ( Wegner N. et al, Immunol. Rev., 233(1) (2010), 34-54 ). It is characterised by inflammation of articular joints leading to debilitating destruction of bone and cartilage.
- a weak genetic association between PAD4 polymorphisms and susceptibility to RA has been suggested, albeit inconsistently, in a number of population studies ( Kochi Y. et al, Ann. Rheum. Dis., 70, (2011),512-515 ).
- PAD4 (along with family member PAD2) has been detected in synovial tissue where it is responsible for the deimination of a variety of joint proteins. This process is presumed to lead to a break of tolerance to, and initiation of immune responses to, citrullinated substrates such as fibrinogen, vimentin and collagen in RA joints.
- ACPA anti-citrullinated protein antibodies
- PAD4 contribute to disease pathogenesis and may also be used as a diagnostic test for RA (e.g. the commercially available CCP2 or cyclic citrullinated protein 2 test).
- increased citrullination may also offer additional direct contributions to disease pathogenesis through its ability to affect directly the function of several joint and inflammatory mediators (e.g. fibrinogen, anti-thrombin, multiple chemokines).
- anti-PAD4 antibodies can be measured and may correlate with a more erosive form of the disease.
- PAD4 inhibitors may also be useful for the reduction of pathological neutrophil activity in a variety of diseases.
- NET Neutrophil Extracellular Trap
- PAD4 inhibitors may therefore have applicability for diseases where NET formation in tissues contributes to local injury and disease pathology.
- Such diseases include, but are not limited to, small vessel vasculitis ( Kessenbrock K. et al, Nat. Med., 15(6), (2009), 623-625 ), systemic lupus erythematosus ( Hakkim A. et al, Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818 and Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52 ), ulcerative colitis ( Savchenko A. et al, Pathol. Int., 61 (5), (2011), 290-7 ), cystic fibrosis, asthma ( Dworski R. et al, J. Allergy Clin.
- NETs may contribute to pathology in diseases affecting the skin, eg in cutaneous lupus erythematosis ( Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52 ) and psoriasis ( Lin A.M. et al., J. Immunol., 187(1), (2011), 490-500 ), so a PAD4 inhibitor may show benefit to tackle NET skin diseases, when administered by a systemic or cutaneous route. PAD4 inhibitors may affect additional functions within neutrophils and have wider applicability to neutrophilic diseases.
- PAD inhibitors for example chloro-amidine
- collagen-induced arthritis Willis V.C. et al, J. Immunol., 186(7), (2011), 4396-4404
- DSS dextran sulfate sodium
- EAE experimental autoimmune encephalomyelitis
- the DSS colitis report also demonstrates that chloro-amidine drives apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be effective more generally in widespread inflammatory diseases.
- PAD4 inhibitors may also be useful in the treatment of cancers ( Slack.J.L. et al, Cell. Mol. Life Sci., 68(4), (2011), 709-720 ). Over-expression of PAD4 has been demonstrated in numerous cancers ( Chang X. et al, BMC Cancer, 9, (2009), 40 ). An anti-proliferative role has been suggested for PAD4 inhibitors from the observation that PAD4 citrullinates arginine residues in histones at the promoters of p53-target genes such as p21, which are involved in cell cycle arrest and induction of apoptosis ( Li P. et al, Mol. Cell Biol., 28(15), (2008), 4745-4758 ).
- PAD4 is the primary PAD family member observed to be resident in the nucleus as well as the cytoplasm. Early evidence that PAD4 may act as a histone demethyliminase as well as a deiminase is inconsistent and unproven. However, it may reduce histone arginine methylation (and hence epigenetic regulation associated with this mark) indirectly via depletion of available arginine residues by conversion to citrulline. PAD4 inhibitors may therefore be useful as epigenetic tools or therapeutics for affecting expression of varied target genes in additional disease settings.
- PAD4 inhibitors may also be effective in controlling citrullination levels in stem cells and may therefore therapeutically affect the pluripotency status and differentiation potential of diverse stem cells including, but not limited to, embryonic stem cells, neural stem cells, haematopoietic stem cells and cancer stem cells.
- the invention is directed to compounds of formula (I): wherein R 1 , R 2 , R 3 , R 4 , A, B, D, R 8 , R 9 , and R 10 are as defined in claim 1, and salts thereof.
- Certain compounds of the invention have been shown to be PAD4 inhibitors and may also show enhanced selectivity for PAD4 with respect to PAD2. For example, certain compounds of the invention indicate 1000-fold selectivity for PAD4 inhibition over PAD2 inhibition.
- Compounds which inhibit PAD4 may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.
- the invention is further directed to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.
- the invention is still further directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of disorders associated therewith.
- R 1 is hydrogen
- R 1 is C 1-6 alkyl.
- R 2 is hydrogen or C 1-6 alkoxy.
- R 2 is C 1-6 alkoxy.
- R 2 is perhalomethyl C 0-5 alkyl-O-.
- R 2 is trifluoromethoxy
- R 3 is hydrogen
- R 3 is C 1-6 alkoxyC 1-6 alkyl.
- R 3 is C 1-6 alkyl.
- R 4 is C 1-6 alkyl, unsubstituted C 3-6 cycloalkylC 1-6 alkyl, or perhalomethylC 1-6 alkyl.
- R 4 is C 1-6 alkyl, unsubstituted C 3-6 cycloalkylC 1-6 alkyl, or perfluoromethylC 1-6 alkyl.
- R 5 is hydrogen
- R 6 is hydrogen
- R 7 is hydrogen, C 1-6 alkoxy, or hydroxy. In one embodiment, R 7 is hydrogen.
- R 8 is hydrogen
- R 9 is hydrogen
- R 9 is hydroxy
- R 10 is hydrogen
- the compound of the invention is selected from the list consisting of:
- the compound of the invention is selected from the list consisting of:
- the compound of the invention is selected from the list consisting of:
- the compound of the invention is selected from the list consisting of:
- the compound of the invention is selected from the list consisting of:
- references herein to compounds of formula (I) are equally-applicable to compounds of formula (I'), for example methods of preparation, compositions, and methods of use.
- 'Alkyl' refers to a saturated hydrocarbon chain having the specified number of carbon atoms.
- C 1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms, for example 1 to 2 carbon atoms.
- Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
- 'Alkyl' includes methyl and ethyl.
- 'Alkoxy' refers to a saturated hydrocarbon chain having the specified number of carbon atoms linked by a single bond to an oxygen atom.
- C 1-6 alkoxy refers to an alkoxy group having from 1 to 6 carbon atoms, for example 1 to 2 carbon atoms, for example 1 carbon atom.
- Alkoxy groups may be straight or branched. Representative branched alkoxy groups have one, two, or three branches.
- 'Alkoxy' includes methoxy.
- 'Cycloalkyl' refers to a saturated hydrocarbon ring having the specified number of member atoms.
- C 3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms, for example 3 member atoms.
- 'Cycloalkyl' includes cyclopropyl.
- Enantiomeric excess' is the excess of one enantiomer over the other expressed as a percentage. In a racemic modification, since both enantiomers are present in equal amounts, the enantiomeric excess is zero (0% ee). However, if one enantiomer were enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
- 'Enantiomerically enriched' refers to products whose enantiomeric excess (ee) is greater than zero.
- 'enantiomerically enriched' refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
- Enantiomerically pure' refers to products whose enantiomeric excess is 99% or greater.
- 'Half-life' refers to the time required for half of a quantity of a substance to be converted to another chemically distinct species in vitro or in vivo.
- Halo' refers to a halogen radical, for example, fluoro, chloro, bromo, or iodo, for example bromo, chloro, or fluoro.
- Perhalomethyl refers to a methyl group in which all of the hydrogen atoms have been replaced with a halogen radical.
- An example of perhalomethyl is perfluoromethyl i.e. CF 3 -.
- 'Heterocyclic' and 'heterocyclyl' refer to saturated or unsaturated monocyclic aliphatic rings containing 5, 6, or 7 ring members including 1 or 2 heteroatoms or to saturated or unsaturated bicyclic aliphatic rings containing 6, 7, or 8 ring members including 1 or 2 heteroatoms.
- 'heterocyclyl groups' are saturated.
- 'heterocyclyl' groups are unsaturated.
- 'Heterocyclyl' groups containing more than one heteroatom may contain different heteroatoms.
- 'Heterocyclyl' groups may be substituted with one or more substituents as defined herein.
- 'Heterocyclyl' includes piperidinyl.
- 'Heteroaryl' refers to aromatic rings containing from 1 to 3 heteroatoms as member atoms in the ring. 'Heteroaryl' groups containing more than one heteroatom may contain different heteroatoms. 'Heteroaryl' groups may be substituted with one or more substituents if so defined herein. The 'heteroaryl' rings have 5 or 6 member atoms. 'Heteroaryl' includes pyrrolopyridinyl and benzimidazolyl.
- Heteroatom' refers to a nitrogen, sulfur, or oxygen atom, for example a nitrogen atom.
- ember atoms' refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
- 'Substituted' in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term 'substituted' includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as rearrangement, cyclisation, or elimination). In certain embodiments, a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
- 'Pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or non-crystalline form, or as a mixture thereof.
- pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethanol, iso -propyl alcohol, N,N-dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
- Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as 'hydrates'. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
- polymorphism i.e. the capacity to occur in different crystalline structures.
- These different crystalline forms are typically known as 'polymorphs'.
- the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
- polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
- the invention also includes isotopically-labelled compounds, which are identical to the compounds of formula (I) and salts thereof, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
- isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 3 H, 11 C, 14 C and 18 F.
- the compounds according to formula (I) contain one or more asymmetric centres (also referred to as a chiral centres) and may, therefore, exist as individual enantiomers, diastereoisomers, or other stereoisomeric forms, or as mixtures thereof.
- Chiral centres such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
- the stereochemistry of a chiral centre present in formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof.
- compounds according to formula (I) containing one or more chiral centres may be used as racemic modifications including racemic mixtures and racemates, enantiomerically-enriched mixtures, or as enantiomerically-pure individual stereoisomers.
- the fragment (Z) of the compounds of formula (I) illustrated below: contains a chiral centre at the junction of the amino-group with the ring (marked with an asterisk (*)).
- the stereochemistry at this chiral centre may be R, S, RS, or any mixture of R and S stereoisomers.
- Individual stereoisomers of a compound according to formula (I) which contain one or more asymmetric centres may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
- stereoisomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
- references herein to compounds of formula (I) and salts thereof covers the compounds of formula (I) as free bases, or as salts thereof, for example as pharmaceutically acceptable salts thereof.
- the invention is directed to compounds of formula (I) as the free base.
- the invention is directed to compounds of formula (I) and salts thereof.
- the invention is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof.
- pharmaceutically acceptable salts of the compounds according to formula (I) may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts of the compounds according to formula (I) may be preferred over the respective free base because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to compounds of formula (I) and pharmaceutically acceptable salts thereof.
- salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable acid.
- Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
- one embodiment of the invention embraces compounds of formula (I) and salts thereof.
- Compounds according to formula (I) contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
- Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids.
- Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, iso -butyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzo
- the compounds of the invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out in the following schemes, and can be readily adapted to prepare other compounds of the invention. Specific compounds of the invention are prepared in the Examples section.
- a compound of formula (I) may be prepared by deprotection of a compound of formula (II). Accordingly, in a first aspect, there is provided a process for the preparation of a compound of formula (I) by deprotection of a compound of formula (II): wherein R 1 , R 2 , R 3 , R 4 , A, B, D, R 8 , R 9 , and R 10 are as hereinbefore defined, and P is a suitable protecting group for amines, for example tert -butoxycarbonyl (Boc), and thereafter, if required, preparing a salt of the compound so formed.
- R 1 , R 2 , R 3 , R 4 , A, B, D, R 8 , R 9 , and R 10 are as hereinbefore defined
- P is a suitable protecting group for amines, for example tert -butoxycarbonyl (Boc)
- a suitable solvent for example dichloromethane
- trifluoroacetic acid for example trifluoroacetic acid
- a suitable temperature for example ambient temperature
- a suitable period of time for example 1-3 hours.
- the reaction mixture is then concentrated under reduced pressure.
- the crude product is then dissolved in a suitable solvent, for example methanol, and loaded onto an ion-exchange cartridge, for example a strong cation-exchange cartridge.
- the product is then eluted as the free base with a suitable solvent, for example 2M ammonia in methanol and the eluant concentrated under reduced pressure to yield a compound of formula (I).
- a compound of formula (II) may be prepared by condensation of a compound of formula (III): wherein R 1 , R 2 , R 3 , R 9 , R 10 , and P are as hereinbefore defined, with a compound of formula (IV) wherein R 4 , A, B, D, and R 8 are as hereinbefore defined.
- a compound of formula (IV) and a suitable peptide coupling reagent for example o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)
- a suitable solvent for example N,N-dimethylformamide
- stirred at a suitable temperature for example ambient temperature, for a suitable period of time, for example 5-10 minutes.
- a solution of a compound of formula (III), and a suitable hindered base for example N,N-di- iso -propylethylamine (DIPEA)
- DIPEA N,N-di- iso -propylethylamine
- a suitable solvent for example N,N-dimethylformamide
- the reaction mixture is diluted with water and partitioned with a suitable organic solvent, for example ether.
- the organic layer is isolated then the aqueous layer re-extracted with ether.
- the combined organic layers are washed with water then dried over sodium sulfate then passed through a hydrophobic frit and concentrated under reduced pressure to give the crude amide intermediate.
- the solid is dried under reduced pressure for 12-24 hours then dissolved in a suitable solvent, for example toluene.
- a suitable organic acid for example acetic acid is added to the reaction mixture and then the mixture is heated to reflux for a suitable period of time, for example which was refluxed for 4-6 hours.
- a suitable aqueous base for example sodium bicarbonate solution is added to the reaction mixture and the organic layer isolated. The aqueous layer is re-extracted with a suitable organic solvent, for example toluene, and the combined organic layers concentrated under reduced pressure to give the crude product.
- the crude material may be purified by, for example, column chromatography.
- a compound of formula (II) may also be prepared by reaction of a compound of formula (XX): wherein R 1 , R 2 , R 3 , R 4 , A, B, D, and R 8 are as hereinbefore defined, with a compound of formula (X) as hereinafter defined.
- a suitable solvent for example N,N-dimethylformamide (DMF)
- a suitable peptide coupling reagent for example o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)
- HATU o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
- DIPEA N,N-di- iso -propylethylamine
- a compound of formula (X) is added in a suitable solvent, for example DMF and the reaction stirred at a suitable temperature, for example ambient temperature, for a suitable period of time, for example 3-8 hours.
- a suitable temperature for example ambient temperature
- a suitable period of time for example 3-8 hours.
- Water and a suitable organic solvent for example diethyl ether are added and the layers separated.
- the aqueous layer is extracted with further organic solvent, for example diethyl ether and the combined organic layers washed with water, dried, for example using anhydrous sodium sulfate, and concentrated under reduced pressure.
- the crude product may be purified for example by column chromatography.
- a compound of formula (III) may be prepared by reduction of a compound of formula (VIII): wherein R 1 , R 2 , R 3 , R 9 , R 10 , and P are as hereinbefore defined.
- a compound of formula (VIII) is dissolved in a suitable solvent, for example ethanol and added to a flushed hydrogenation flask containing a suitable catalyst, for example palladium on carbon.
- a suitable solvent for example ethanol
- the resultant mixture is flushed with nitrogen/vacuum, then stirred under an atmosphere of hydrogen at a suitable temperature, for example ambient temperature, for a suitable period of time, for example 24 hours.
- the reaction mixture is then flushed from the hydrogen atmosphere with nitrogen/vacuum.
- Celite is added and the mixture stirred for a suitable period of time, for example 2-5 minutes, then filtered under reduced pressure.
- the solution is concentrated under reduced pressure to give a crude product that may be purified by, for example, chromatography.
- a compound of formula (VIII) may be prepared by reaction of a compound of formula (IX): wherein R 1 , R 2 , and R 3 are as hereinbefore defined, with a compound of formula (X): wherein R 9 , R 10 , and P are as hereinbefore defined.
- a suitable peptide coupling reagent for example o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in a suitable solvent, for example N,N-dimethylformamide, is added a suitable hindered base, for example N,N-di-isopropylethylamine (DIPEA) and the reaction stirred at a suitable temperature, for example ambient temperature, for a suitable period of time, for example 12-18 hours.
- a suitable solvent for example N,N-dimethylformamide
- DIPEA N,N-di-isopropylethylamine
- a compound of formula (IX) may be prepared by hydrolysis of a compound of formula (XI): wherein Rb is C 1-6 alkyl and R 1 , R 2 , R 3 are as hereinbefore defined.
- a compound of formula (XI) is dissolved in a suitable solvent, for example a 1:1 v/v ratio of tetrahydrofuran and water.
- a suitable base for example lithium hydroxide
- the reaction stirred at a suitable temperature, for example ambient temperature, for a suitable period of time, for example 12-18 hours.
- the reaction mixture was cooled to a suitable temperature, for example 0°C and acidified by the addition of a suitable aqueous mineral acid, for example 5M HCI solution, until the pH reaches about 5.
- the slurry is filtered and the product residue washed with distilled water and dried.
- a compound of formula (XI) may be prepared by reaction of a compound of formula (XIV): wherein Rb, R 1 , and R 2 , are as hereinbefore defined and L is a suitable leaving group, for example a halo group, for example chloro, with a compound of formula (XIII): R 3 -NH 2 (XIII) wherein R 3 is as hereinbefore defined.
- a compound of formula (XIV) is dissolved in a suitable solvent, for example N,N-dimethylformamide (DMF) and cooled to a suitable temperature, for example about 0°C in an ice/water bath.
- a solution of a compound of formula (XIII) in a suitable solvent, for example tetrahydrofuran is added dropwise with vigorous stirring and the mixture flushed with nitrogen and heated to a suitable temperature, for example 70-90°C for a suitable period of time, for example 3 hours.
- the mixture is allowed to cool to a suitable temperature, for example ambient temperature, over a suitable period of time, for example 60-70 hours.
- the reaction mixture is diluted with water and filtered under reduced pressure to give a compound of formula (XI).
- a compound of formula (IV) wherein R 4 is other than hydrogen may be prepared by hydrolysis of a compound of formula (V): wherein R a is C 1-6 alkyl, R 4 , is other than hydrogen, and A, B, D, and R 8 are as hereinbefore defined.
- a suitable solvent for example a mixture of methanol, tetrahydrofuran (THF), and water
- a suitable base for example lithium hydroxide monohydrate
- a suitable temperature for example ambient temperature under an inert atmosphere, for example an atmosphere of nitrogen, for a suitable period of time, for example 1-2 hours.
- the mixture is concentrated under reduced pressure, then treated with a suitable aqueous mineral acid, for example 2N HCI, and the product isolated by filtration.
- a compound of formula (V) wherein R 4 is other than hydrogen may be prepared by alkylation of a compound of formula (IV) wherein R 4 is hydrogen i.e. a compound of formula (VI): wherein A, B, D, and R 8 are as hereinbefore defined.
- a suitable organic solvent for example dimethyl sulfoxide (DMSO) is added to a flask containing a suitable base, for example potassium hydroxide and the mixture stirred under an inert atmosphere, for example an atmosphere of nitrogen, for a suitable period of time, for example 8-12 minutes.
- a compound of formula (VI) and a suitable alkylating agent, for example bromoethane is added and the mixture stirred at a suitable temperature, for example ambient temperature, under the inert atmosphere for a suitable period of time, for example 18-24 hours.
- the reaction is quenched by the slow careful addition of water.
- a suitable organic solvent for example diethyl ether, is added and the reaction mixture separated into the organic and aqueous layers.
- aqueous layer is further extracted with a suitable organic solvent, for example diethyl ether, and the combined organic layers dried, for example by passing through a hydrophobic frit, and concentrated under reduced pressure to give a compound of formula (V) wherein R 4 is other than hydrogen.
- a suitable organic solvent for example diethyl ether
- a compound of formula (II) may also be prepared by condensation with a compound of formula (VII). Accordingly, in a further aspect, there is provided a process for the preparation of a compound of formula (II) by reaction of a compound of formula (VII): wherein R 4 , A, B, D, and R 8 , are as hereinbefore defined, with a compound of formula (VIII) as hereinbefore defined.
- a suitable solvent for example ethanol
- a suitable reducing agent for example sodium dithionite
- a suitable solvent for example water
- the reaction mixture is concentrated under vacuum then diluted with a suitable solvent, for example dichloromethane and water added.
- the organic layer is collected and the aqueous layer washed with further solvent, for example dichloromethane.
- the organic layers are combined, back washed with water, collected, dried with, for example anhydrous sodium sulfate, filtered through a hydrophobic frit and concentrated under vacuum to yield the crude product.
- the crude product may be purified by conventional means, for example chromatography.
- a compound of formula (VII) wherein R 4 is other than hydrogen may be prepared by reaction of a compound of formula (VII) wherein R 4 is hydrogen by reaction with a compound of formula (XV): R 4 -M (XV) wherein R 4 is as hereinbefore defined and M is a suitable leaving group, for example a halo group, for example iodo, or an alkylsulfonyl group, for example trifluoromethanesulfonyl.
- a suitable organic medium for example N,N-dimethylformamide stirred under an inert atmosphere, for example an atmosphere of nitrogen, at a suitable temperature, for example 20°C
- a compound of formula (XV) dropwise over a suitable period of time for example 0.5-1 minute.
- the reaction mixture is stirred at a suitable temperature, for example ambient temperature. for a suitable period of time, for example 1 hour.
- the reaction mixture is quenched with water, partitioned between a suitable organic solvent, for example dichloromethane, and water.
- the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane.
- the organic phase is washed with saturated brine, dried over, for example sodium sulfate, and evaporated in vacuo to give the crude product.
- the crude product may be purified by conventional means, for example chromatography.
- a compound of formula (VII) wherein R 4 is hydrogen may be prepared by deprotection of a compound of formula (XVI): wherein R c is an aryl group, for example phenyl, and A, B, D, and R 8 are as hereinbefore defined.
- a suitable base for example potassium hydroxide
- a suitable organic solvent for example methanol
- a suitable solvent for example methanol
- a suitable period of time for example 0.5-1 minute.
- the mixture is stirred at a suitable temperature, for example ambient temperature, until the starting material is consumed.
- the reaction mixture is then diluted with water and then a suitable organic solvent, for example dichloromethane is added.
- the pH is adjusted to 7 with a suitable mineral acid, for example concentrated hydrochloric acid, and extracted with further organic solvent, for example dichloromethane.
- the organic phase is then washed, dried, and the solvent removed to give a compound of formula (VII).
- a compound of formula (XVI) may be prepared from a compound of formula (XVII) wherein R c , A, B, D, and R 8 are as hereinbefore defined.
- a suitable organic base for example diisopropylamine
- a suitable anhydrous organic solvent for example anhydrous tetrahydrofuran
- stirred under an inert atmosphere for example an atmosphere of nitrogen
- a suitable temperature for example -78°C
- a suitable base for example n-butyllithium
- the reaction mixture is stirred at a suitable temperature, for example -78°C for a suitable period of time, for example 20-40 minutes, then warmed to a suitable temperature, for example ambient temperature, and stirred for a suitable period of time, for example 45-90 minutes.
- the reaction mixture is stirred at a suitable temperature, for example -30°C, for a suitable period of time, for example 2-3 hours, then a suitable organic solvent, for example N,N-dimethylformamide is added dropwise over a suitable period of time, for example 1 minute.
- a suitable temperature for example -30°C for a further suitable period of time, for example 1.5-3 hours.
- the reaction mixture is quenched with water and partitioned between a suitable organic solvent, for example dichloromethane, and water.
- the organic phase is washed, dried, and evaporated to give a crude compound of formula (XVI), which may be purified by conventional means, for example, recrystallisation.
- a compound of formula (XVII) may be prepared by reaction of a compound of formula (XVIII): wherein A, B, D, and R 8 are as hereinbefore defined, with a compound of formula (XIX): R c SO 2 -Q (XIX) wherein Rc is as hereinbefore defined and Q is a suitable leaving group, for example a halo group, for example chloro.
- a suitable organic solvent for example tetrahydrofuran
- a suitable base for example sodium hydride portionwise over a suitable period of time, for example 5 minutes
- an inert atmosphere for example an atmosphere of nitrogen
- a suitable temperature for example 0°C.
- the reaction mixture is stirred at a suitable temperature, for example 0°C for a suitable period of time, for example 30-45 minutes, then a compound of formula (XIX) is added dropwise under an inert atmosphere, for example an atmosphere of nitrogen, at a suitable temperature, for example 0°C, then stirred for a suitable period of time, for example 1.5-3 hours at a suitable temperature, for example ambient temperature, until the starting material had been completely consumed.
- a suitable temperature for example 0°C
- a suitable period of time for example 1.5-3 hours at a suitable temperature, for example ambient temperature
- a compound of formula (XX) may be prepared by hydrolysis of a compound of formula (XXI): wherein R 1 , R 2 , R 3 , R 4 , A, B, D, and R 8 are as hereinbefore defined and R d is an alkyl group, for example C 1-6 alkyl,
- a compound of formula (XXI) is dissolved in a suitable solvent, for example a mixture of a suitable organic solvent and water, for example a mixture of tetrahydrofuran (THF) and water, for example in a 1:1 ratio.
- a suitable base for example lithium hydroxide anhydrous and the reaction stirred at a suitable temperature, for example ambient temperature, for a suitable period of time, for example 15-24 hours.
- the reaction mixture is then neutralised by the addition of a suitable acid, for example 2M hydrochloric acid.
- the suspension is filtered and the residue washed with water and dried in vacuo to afford a compound of formula (XX).
- a compound of formula (XXI) may be prepared by reaction of a compound of formula (VII) as hereinbefore defined with a compound of formula (XI) as hereinbefore defined.
- a solution of a suitable reducing agent for example sodium hydrosulfite
- a suitable solvent for example water
- a suitable medium for example; ethanol
- the reaction mixture is heated, for example in a microwave oven, to a suitable temperature, for example, 90-110°C for a suitable period of time, for example 3-6 hours.
- the reaction mixture is diluted with a suitable solvent, for example dichloromethane, dried, for example using anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product.
- the crude product may be purified by, for example, column chromatography.
- a compound of formula (X) wherein R 9 is hydroxy may be prepared by hydrogenolysis of a compound of formula (XXII): wherein P and R 10 are as hereinbefore defined and P 1 is a protecting group, for example a carboxybenzyl group.
- a solution of a compound of formula (XXII) in a suitable solvent for example ethanol is added to a hydrogenation flask containing a suitable catalyst, for example 10% palladium on carbon, under an inert atmosphere, for example an atmosphere of nitrogen.
- a suitable catalyst for example 10% palladium on carbon
- the flask is then evacuated and back-filled with hydrogen.
- the system is closed and the mixture allowed to stir under an atmosphere of hydrogen for a suitable period of time, for example 12-18 hours.
- the reaction mixture was filtered and washed with a suitable solvent, for example ethanol, followed by a further solvent wash with, for example ethyl acetate.
- the combined filtrate is concentrated under reduced pressure to afford a compound of formula (X).
- a compound of formula (XXII) wherein the -OH group and -NHP groups are cis with respect to each other may be prepared by hydrolysis of a compound of formula (XXIII): wherein P and P 1 , and R 10 are as hereinbefore defined and P 2 is a suitable protecting group, for example a benzoyl group.
- a solution of a suitable base, for example potassium carbonate in a suitable solvent, for example water is added to a solution of a compound of formula (XXIII) in a suitable solvent, for example ethanol, and the mixture stirred at a suitable temperature, for example 60-70°C for 18-24 hours.
- the reaction mixture is concentrated under reduced pressure, diluted with water, and extracted using a suitable solvent, for example dichloromethane.
- the organic extracts are combined and dried using, for example anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude compound of formula (XXII) wherein the -OH group and -NHP groups are cis with respect to each other.
- the crude product may be purified by, for example, column chromatography.
- a compound of formula (XXIII) wherein the P 2 O- and -NHP groups are cis with respect to each other may be prepared from a compound of formula (XXII) where the HO- and -NHP groups are trans with respect to each other via the Mitsunobu reaction.
- a compound of formula (XXII) wherein the -OH group and -NHP groups are trans with respect to each other may be prepared by hydrolysis of a compound of formula (XXIV): wherein P 1 and R 10 are as hereinbefore defined.
- a solution of a compound of formula (XIV) in a suitable basic solvent mixture for example a mixture of aqueous ammonium hydroxide solution and a suitable organic solvent, for example ethanol is stirred at a suitable temperature, for example 60-80°C for a suitable period of time, for example 4-6 hours.
- the reaction mixture is concentrated under reduced pressure, diluted with brine, and the organic layer extracted into a suitable solvent, for example dichloromethane.
- the combined organic layers are dried using, for example anhydrous sodium sulfate, and concentrated under reduced pressure to give the intermediate primary amine.
- the residue is diluted with a suitable solvent, for example dichloromethane and a suitable base, for example triethylamine, and the precursor to a suitable protecting group, for example di- tert -butyl dicarbonate.
- a suitable solvent for example dichloromethane and a suitable base, for example triethylamine
- a suitable protecting group for example di- tert -butyl dicarbonate.
- the reaction is allowed to stir for a suitable period of time, for example 1-3 hours, quenched with, for example, saturated aqueous ammonium chloride solution, and the layers separated.
- the combined organic layers are dried using, for example, a hydrophobic frit and the solvent was removed under reduced pressure to yield a compound of formula (XXII) wherein the -OH group and - NHP groups are trans with respect to each other.
- a compound of formula (XXIV) may be prepared by reaction of a suitable peracid, for example 3-chlorobenzoperoxoic acid, with a compound of formula (XXV): wherein P 1 and R 10 are as hereinbefore defined.
- a suitable peracid for example 3-chlorobenzoperoxoic acid
- a stirred solution of a compound of formula (XXV) available, for example, from Fluorochem, Hadfield, Derbyshire, UK
- a suitable anhydrous solvent for example anhydrous dichloromethane
- the resulting mixture is allowed to reach ambient temperature and stirred for a suitable period of time, for example 12-24 hours.
- Water is added to the reaction mixture and the layers partitioned.
- the organic layer is added to a stirred solution of a reducing agent for example an aqueous solution of sodium metabisulfite to destroy excess peracid.
- the layers are separated and aqueous layer washed with a suitable solvent, for example dichloromethane.
- a suitable solvent for example dichloromethane.
- the combined organic layers are then dried, for example using anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product, which may be purified by chromatography.
- conventional methods of heating and cooling may be employed, for example temperature-regulated oil-baths or temperature-regulated hot-blocks, and ice/salt baths or dry ice/acetone baths respectively.
- Conventional methods of isolation for example extraction from or into aqueous or non-aqueous solvents may be used.
- Conventional methods of drying organic solvents, solutions, or extracts such as shaking with anhydrous magnesium sulfate, or anhydrous sodium sulfate, or passing through a hydrophobic frit, may be employed.
- Conventional methods of purification for example crystallisation and chromatography, for example silica chromatography or reverse-phase chromatography, may be used as required.
- Crystallisation may be performed using conventional solvents such as ethyl acetate, methanol, ethanol, or butanol, or aqueous mixtures thereof. It will be appreciated that specific reaction times and temperatures may typically be determined by reaction-monitoring techniques, for example thin-layer chromatography and LC-MS.
- the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography or VCD (vibrational circular dichroism) analysis.
- the compounds of the invention are inhibitors of PAD4.
- Compounds which inhibit PAD4 may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.
- the methods of treatment of the invention comprise administering a safe and effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
- Individual embodiments of the invention include methods of treating any one of the above-mentioned disorders by administering a safe and effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
- 'treat' in reference to a disorder means: (1) to ameliorate or prevent the disorder or one or more of the biological manifestations of the disorder, (2) to interfere with (a). one or more points in the biological cascade that leads to or is responsible for the disorder, or (b). one or more of the biological manifestations of the disorder, (3) to alleviate one or more of the symptoms or effects associated with the disorder, or (4) to slow the progression of the disorder or one or more of the biological manifestations of the disorder.
- 'treatment' of a disorder includes prevention of the disorder. It will be appreciated that 'prevention' is not an absolute term. In medicine, 'prevention' is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a disorder or biological manifestation thereof, or to delay the onset of such disorder or biological manifestation thereof.
- 'safe and effective amount' in reference to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
- a safe and effective amount of a compound will vary with the particular compound chosen (for example, the potency, efficacy, and half-life of the compound will be considered); the route of administration chosen; the disorder being treated; the severity of the disorder being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
- 'patient' refers to a human (including adults and children) or other animal. In one embodiment, 'patient' refers to a human.
- the compounds of formula (I), or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including both systemic administration and topical administration.
- Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration.
- Parenteral administration refers to routes of administration other than enteral or transdermal, and is typically by injection or infusion.
- Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
- Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhaled and intranasal administration. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered orally.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered topically. In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered by inhalation. In a further embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered intranasally.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. In one embodiment, a dose is administered once per day. In a further embodiment, a dose is administered twice per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
- suitable dosing regimens including the duration such regimens are administered, for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
- Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.1 mg to 10mg per kg of total body weight, for example from 1 mg to 5mg per kg of total body weight. For example, daily dosages for oral administration may be from 5mg to 1 g per patient, such as 5mg to 500mg per patient, or 5mg to 250mg.
- the invention provides a safe and effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by inappropriate PAD4 activity.
- the disorder mediated by inappropriate PAD4 activity is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.
- the disorder mediated by inappropriate PAD4 activity is rheumatoid arthritis.
- the disorder mediated by inappropriate PAD4 activity is systemic lupus.
- the disorder mediated by inappropriate PAD4 activity is vasculitis.
- the disorder mediated by inappropriate PAD4 activity is cutaneous lupus erythematosis.
- the disorder mediated by inappropriate PAD4 activity is psoriasis.
- a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis of.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by inappropriate PAD4 activity.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic lupus. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of vasculitis. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cutaneous lupus erythematosis.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.
- the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PAD4 activity.
- the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis.
- the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis.
- the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of systemic lupus.
- the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of vasculitis.
- the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cutaneous lupus erythematosis.
- the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of psoriasis.
- the invention provides a pharmaceutical composition for the treatment or prophylaxis of a disorder mediated by inappropriate PAD4 activity comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides a pharmaceutical composition for the treatment or prophylaxis of systemic lupus comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides a pharmaceutical composition for the treatment or prophylaxis of vasculitis comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides a pharmaceutical composition for the treatment or prophylaxis of cutaneous lupus erythematosis comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides a pharmaceutical composition for the treatment or prophylaxis of psoriasis comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof
- compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
- the invention is directed to pharmaceutical compositions for the treatment or prophylaxis of a disorder mediated by inappropriate PAD4 activity comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be extracted and then given to the patient such as with powders or syrups.
- the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical compositions of the invention typically may contain, for example, from 0.25mg to 1 g, or from 0.5mg to 500mg, or from 1mg to 100mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- compositions of the invention typically contain one compound of formula (I) or a pharmaceutically acceptable salt thereof.
- 'pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
- Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of formula (I) or a pharmaceutically acceptable salt thereof when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
- each excipient must of course be pharmaceutically acceptable e.g. of sufficiently high purity.
- dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols, solutions, and dry powders; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
- Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
- suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
- certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
- Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
- Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of formula (I) or pharmaceutically acceptable salts thereof once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
- Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
- Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavouring agents, flavour-masking agents, colouring agents, anti-caking agents, humectants, chelating agents, plasticisers, viscosity increasing agents, antioxidants, preservatives, stabilisers, surfactants, and buffering agents.
- excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavouring agents, flavour-masking agents, colouring agents, anti-caking agents, humectant
- Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
- resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company ), The Handbook of Pharmaceutical Additives (Gower Publishing Limited ), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press ).
- compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company ).
- the invention is directed to process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically-acceptable excipients which comprises mixing the ingredients.
- a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by, for example, admixture at ambient temperature and atmospheric pressure.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for oral administration. In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for inhaled administration. In a further embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for intranasal administration.
- the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a diluent or filler.
- Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
- the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
- the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
- the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
- dosage unit formulations for oral administration can be microencapsulated.
- the composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be coupled with soluble polymers as targetable drug carriers.
- soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- biodegradable polymers useful in achieving controlled release of a drug
- a drug for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- the invention is directed to a liquid oral dosage form.
- Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- Syrups can be prepared by dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
- Suspensions can be formulated by dispersing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a non-toxic vehicle.
- Solubilisers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavour additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
- the invention is directed to a dosage form adapted for administration to a patient by inhalation, for example, as a dry powder, an aerosol, a suspension, or a solution composition.
- Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as a finely divided powder together with one or more pharmaceutically-acceptable excipients as finely divided powders.
- Pharmaceutically-acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.
- the finely divided powder may be prepared by, for example, micronisation and milling.
- the size-reduced (eg micronised) compound can be defined by a D 50 value of about 1 to about 10 microns (for example as measured using laser diffraction).
- the dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form.
- RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position.
- the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.
- the dry powder may be presented in capsules (e.g. gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI).
- MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament.
- the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form.
- the blisters are typically arranged in regular fashion for ease of release of the medicament therefrom.
- the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape.
- Each capsule, cartridge, or blister may, for example, contain between 200 ⁇ g-10mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
- Aerosols may be formed by suspending or dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a liquified propellant.
- Suitable propellants include halocarbons, hydrocarbons, and other liquified gases.
- propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane.
- Aerosols comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.
- MDI metered dose inhaler
- the aerosol may contain additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
- additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
- a pharmaceutical aerosol formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a cosolvent.
- a pharmaceutical aerosol formulation wherein the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
- compositions of the invention may be buffered by the addition of suitable buffering agents.
- Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
- a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
- Each capsule or cartridge may generally contain from 200 ⁇ g to 10mg of the compound of formula (I) or pharmaceutically acceptable salt thereof.
- the compound of formula (I) or pharmaceutically acceptable salt thereof may be presented without excipients such as lactose.
- the proportion of the active compound of formula (I) or pharmaceutically acceptable salt thereof in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.01 to 10% by weight. Generally, for most types of preparations, the proportion used will be within the range of from 0.05 to 1%, for example from 0.1 to 0.5%.
- Aerosol formulations are preferably arranged so that each metered dose or 'puff' of aerosol contains from 20 ⁇ g to 10mg, preferably from 20 ⁇ g to 5mg, more preferably from about 20 ⁇ g to 0.5mg of a compound of formula (I). Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.
- the overall daily dose with an aerosol will be within the range from 100 ⁇ g to 10mg, for example from 200 ⁇ g to 5mg.
- the overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that delivered with aerosol formulations.
- the particle size of the particulate (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and in particular in the range of from 1 to 10 microns, such as from 1 to 5 microns, more preferably from 2 to 3 microns.
- the formulations of the invention may be prepared by dispersal or dissolution of the medicament and a compound of formula (I) or a pharmaceutically acceptable salt thereof in the selected propellant in an appropriate container, for example, with the aid of sonication or a high-shear mixer.
- the process is desirably carried out under controlled humidity conditions.
- the chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art.
- the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product.
- Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.
- the stability of the suspension aerosol formulations according to the invention may be measured by conventional techniques, for example, by measuring flocculation size distribution using a back light scattering instrument or by measuring particle size distribution by cascade impaction or by the 'twin impinger' analytical process.
- reference to the 'twin impinger' assay means 'Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A' as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C.
- Such techniques enable the 'respirable fraction' of the aerosol formulations to be calculated.
- One method used to calculate the 'respirable fraction' is by reference to 'fine particle fraction' which is the amount of active ingredient collected in the lower impingement chamber per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above.
- MDI means a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap.
- MDI system includes a suitable channelling device. Suitable channelling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.
- MDI canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, aluminium or an alloy thereof which may optionally be anodised, lacquer-coated and/or plastic-coated (for example incorporated herein by reference WO 96/32099 wherein part or all of the internal surfaces are coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers), which container is closed with a metering valve.
- the cap may be secured onto the can via ultrasonic welding, screw fitting or crimping.
- MDIs taught herein may be prepared by methods of the art (e.g. see Byron, above and WO 96/32099 ).
- the canister is fitted with a cap assembly, wherein a drug-metering valve is situated in the cap, and said cap is crimped in place.
- the metallic internal surface of the can is coated with a fluoropolymer, more preferably blended with a non-fluoropolymer.
- the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES).
- the whole of the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES).
- the metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.
- the gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
- Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. SpraymiserTM).
- the MDIs may also be used in conjunction with other structures such as, without limitation, overwrap packages for storing and containing the MDIs, including those described in U.S. Patent Nos. 6,119,853 ; 6,179,118 ; 6,315,112 ; 6,352,152 ; 6,390,291 ; and 6,679,374 , as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431,168 .
- a metering valve is crimped onto an aluminium can to form an empty canister.
- the particulate medicament is added to a charge vessel and liquefied propellant together with the optional excipients is pressure filled through the charge vessel into a manufacturing vessel.
- the drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
- a metering valve is crimped onto an aluminium can to form an empty canister.
- the liquefied propellant together with the optional excipients and the dissolved medicament is pressure filled through the charge vessel into a manufacturing vessel.
- an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure the formulation does not vaporise, and then a metering valve crimped onto the canister.
- each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
- Suspensions and solutions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered to a patient via a nebuliser.
- the solvent or suspension agent utilized for nebulization may be any pharmaceutically-acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof.
- Saline solutions utilize salts which display little or no pharmacological activity after administration.
- organic salts such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.
- alkali metal or ammonium halogen salts e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
- organic acids e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
- the compound of formula (I) or pharmaceutically acceptable salt thereof may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid.
- Preservatives may be added such as benzalkonium chloride or benzoic acid and salts thereof.
- Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulfosuccinate, oleic acid and sorbitan esters.
- the invention is directed to a dosage form adapted for intranasal administration.
- Formulations for administration to the nose may include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable formulations contain water as the diluent or carrier for this purpose. Aqueous formulations for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated as a fluid formulation for delivery from a fluid dispenser, for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
- a fluid dispenser for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
- Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations.
- the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity.
- a fluid dispenser of the aforementioned type is described and illustrated in WO 05/044354 , the entire content of which is hereby incorporated herein by reference.
- the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation.
- the housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing.
- the fluid dispenser is of the general type illustrated in Figures 30-40 of WO 05/044354 .
- compositions adapted for intranasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
- suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oil solutions of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
- compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the patient for a prolonged period of time.
- the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986 ).
- compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
- Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
- bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
- Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
- Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
- Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
- Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
- Topical preparations may be administered by one or more applications per day to the affected area. Over skin areas, occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.
- compositions may be applied as a topical ointment or cream.
- the compound of formula (I) or a pharmaceutically acceptable salt thereof may be employed with either a paraffinic or a water-miscible ointment base.
- the compound of formula (I) or pharmaceutically acceptable salt thereof may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
- compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
- LCMS was conducted on an Acquity UPLC BEH C 18 column (50mm x 2.1mm i.d. 1.7 ⁇ m packing diameter) at 40 degrees centigrade, eluting with 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution (Solvent A) and acetonitrile (Solvent B) using the following elution gradient: 0-1.5min: 1-97% B, 1.5-1.9min: 97% B, 1.9-2.0min: 100% B at a flow rate of 1ml/min.
- the UV detection was a summed signal from wavelength of 210nm to 350nm.
- the mass spectra were recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray. lonisation data were rounded to the nearest integer.
- LCMS was conducted on an Acquity UPLC BEH C 18 column (50mm x 2.1mm i.d. 1.7 ⁇ m packing diameter) at 40 degrees centigrade, eluting with 0.1 % v/v solution of formic acid in water (Solvent A) and 0.1% v/v solution of formic acid in acetonitrile (Solvent B) using the following elution gradient: 0-1.5min: 3-100% B, 1.5-1.9min: 100% B, 1.9-2.0min: 3% B at a flow rate of 1ml/min.
- the UV detection was a summed signal from wavelength of 210nm to 350nm.
- the mass spectra were recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray. lonisation data were rounded to the nearest integer.
- LCMS was conducted on an Acquity UPLC BEH C 18 column (50mm x 2.1mm i.d. 1.7 ⁇ m packing diameter) at 40 degrees centigrade, eluting with 0.1 % v/v solution of trifluoroacetic acid in water (Solvent A) and 0.1 % v/v solution of trifluoroacetic acid in acetonitrile (Solvent B) using the following elution gradient: 0-1.5min: 3-100% B, 1.5-1.9min: 100% B, 1.9-2.0min: 3% B at a flow rate of 1ml/min.
- the UV detection was a summed signal from wavelength of 210nm to 350nm.
- the mass spectra were recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray. lonisation data were rounded to the nearest integer.
- LCMS was conducted on a HALO C 18 column (50mm x 4.6mm i.d. 2.7 ⁇ m packing diameter) at 40 degrees centigrade, eluting with 0.1% v/v solution of formic acid in water (Solvent A) and 0.1 % v/v solution of formic acid in acetonitrile (Solvent B) using the following elution gradient: 0-1.8min: 5% B, 1.8-2.01 min: 100% B, 2.01-2.8min: 5% B at a flow rate of 1.5ml/min.
- the UV detection was a summed signal at wavelength: 214nm and 254nm.
- MS Ion Source: ESI; Detector Voltage: 1.4 KV; Heat Block temp.: 250°C; CDL temp.: 250°C; Nebuliser Gas Flow: 1.5 mL/min.
- LCMS was conducted on a HALO C 18 column (50mm x 4.6mm i.d. 2.7 ⁇ m packing diameter) at 40 degrees centigrade, eluting with 0.1% v/v solution of formic acid in water (Solvent A) and 0.1 % v/v solution of formic acid in acetonitrile (Solvent B) using the following elution gradient: 0-1min: 5% B, 1-2.01min: 95% B, 2.01-2.5min: 5% B at a flow rate of 1.8ml/min.
- the UV detection was a summed signal at wavelength: 214nm and 254nm.
- GCMS was conducted on an Agilent 6890/5973 GCMS equipment with an Agilent capillary column HP-5 (0.25um x 30m, i.d. 0.25mm).
- the initial temperature is 50°C.
- the equilibration time is 0.50min.
- the initial time is 1.00min.
- the temperature then increase to 180°C with a rate of 10°/min, then rise to 240°C with a rate of 20°C/min, then hold 240°C for 5.00min.
- the injection mode is splitless.
- the gas flow is 1.00ml/min and the total flow is 23.2ml/min.
- the average velocity is 36cm/sec.
- the acquisition mode is scan.
- the ionization method is 70eV EI (Electronic Ionization).
- Silica chromatography techniques include either automated (Flashmaster, Biotage SP4) techniques or manual chromatography on pre-packed cartridges (SPE) or manually-packed flash columns.
- MDAP mass-directed autopreparative chromatography
- the HPLC analysis is conducted on an XBridge C 18 column (100mm x 30mm i.d. 5 ⁇ m packing diameter) at ambient temperature, eluting with 10mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution (Solvent A) and acetonitrile (Solvent B) using the following elution gradient: Time (min) Flow Rate (ml/min) % A % B 0 40 85 15 1 40 85 15 20 40 45 55 21 40 1 99 25 40 1 99
- the UV detection is an averaged signal from wavelength of 210nm to 350nm.
- the mass spectra are recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray.
- lonisation data are rounded to the nearest integer.
- MDAP Method C
- the HPLC analysis is conducted on a Sunfire C 18 column (150mm x 30mm i.d. 5 ⁇ m packing diameter) at ambient temperature, eluting with 0.1% v/v solution of trifluoroacetic acid in water (Solvent A) and 0.1 % v/v solution of trifluoroacetic acid in acetonitrile (Solvent B) using the following elution gradient: Time (min) Flow Rate (ml/min) % A % B 0 40 100 0 3 40 100 0 3.5 30 100 0 24.5 30 70 30 25 30 1 99 32 30 1 99
- the UV detection is an averaged signal from wavelength of 210nm to 350nm.
- the mass spectra are recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray. lonisation data are rounded to the nearest integer. MDAP (Method D).
- the HPLC analysis is conducted on a Sunfire C 18 column (150mm x 30mm i.d.
- the HPLC analysis was conducted on an XBridge C18 column (100mm x 30mm i.d. 5 ⁇ m packing diameter) at ambient temperature, eluting with 10mM Ammonium Bicarbonate in water adjusted to pH 10 with Ammonia solution (Solvent A) and Acetonitrile (Solvent B) using an elution gradient of between 0 and 100% Solvent B over 15 or 25 minutes.
- the UV detection was an averaged signal from wavelength of 210nm to 350nm.
- the mass spectra were recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray. lonisation data was rounded to the nearest integer. MDAP (Method F).
- the HPLC analysis was conducted on a Sunfire C18 column (150mm x 30mm i.d. 5 ⁇ m packing diameter) at ambient temperature, eluting with 0.1% v/v solution of Trifluoroacetic Acid in Water (Solvent A) and 0.1 % v/v solution of Trifluoroacetic Acid in Acetonitrile (Solvent B) using an elution gradient of between 0 and 100% Solvent B over 15 or 25 minutes.
- the UV detection was an averaged signal from wavelength of 210nm to 350nm.
- the mass spectra were recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray. lonisation data was rounded to the nearest integer.
- MDAP Method G
- the HPLC analysis was conducted on a Sunfire C18 column (150mm x 30mm i.d. 5 ⁇ m packing diameter) at ambient temperature, eluting with 0.1% formic acid in water (Solvent A) and 0.1% formic acid in acetonitrile (Solvent B) using an elution gradient of between 0 and 100% Solvent B over 15 or 25 minutes.
- the UV detection was an averaged signal from wavelength of 210nm to 350nm.
- the mass spectra were recorded on a Waters ZQ Mass Spectrometer using Alternate-scan Positive and Negative Electrospray. lonisation data was rounded to the nearest integer.
- Method A Chiral Analytical Chromatography Column Chiralpak AD-H, 250 ⁇ 4.6 mm
- n-Hexane B Ethanol Gradient Profile 90:10 mobile phase A:B Flow Rate 1 mL/min Column Temperature 20°C Detection wavelength 215 nm or UV DAD (300nm (bandwidth 180nm, reference 550nm (bandwidth 100nm))
- Method B Chiral Preparative Chromatography Column Chiralpak AD-H, 250 ⁇ 30 mm, 5 ⁇ m [ADH10029-01]
- Mobile Phase A: n-Hexane B Ethanol Gradient Profile Stepped Isocratic system - 90:10 mobile phase A:B Run Time 20 min Flow Rate 45 mL/min Column Temperature 20°C Detection UV DAD (300nm (bandwidth 180nm, reference 550nm (bandwidth 100nm))
- the reaction was quenched by addition of water (150 mL). After addition of Et 2 O (150 mL), the layers were separated. The aqueous layer was further extracted with Et 2 O (3 x 150 mL) and the combined organic layers were washed with H 2 O. The combined water layers were extracted with Et 2 O (150 mL). The organic layers collected were combined, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was loaded in dichloromethane on two 100g SNAP silica cartridge and purified by SP4, eluting with 0-30% ethyl acetate/cyclohexane gradient.
- Methylamine (2M in THF) (23.19 mL, 46.4 mmol) was added to a solution of methyl 4-chloro-3-nitrobenzoate (5 g, 23.19 mmol) (available, for example, from Lancaster Synthesis Ltd.) in N,N-dimethylformamide (DMF) (8 mL) at rt under nitrogen.
- the reaction mixture was heated to 80°C and stirred overnight.
- LCMS showed major peak product, but reaction had not gone to completion.
- Further methylamine (2M in THF, 10ml) was added and the reaction heated to 90°C for 6 h. Further methylamine (2M in THF, 6ml) was added and the reaction stirred for 1 h at rt and 72 h at 70°C.
- 3-Chlorobenzoperoxoic acid (16.79 g, 97 mmol) was added portionwise under an atmosphere of nitrogen to a stirred solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (15.1 g, 69.5 mmol) (available, for example, from Fluorochem) in anhydrous dichloromethane (DCM) (100 mL) cooled using an ice bath. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixture and the layers were partitioned. The organic layer was added dropwise to a stirred 5% aqueous solution of NaS 2 O 5 (200 mL).
- DCM dichloromethane
- Reagent/Solvent Reaction 1 Reaction 2 Reaction 3 Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (A) 4.37 g, 18.73 mmol 4.45 g, 19.08 mmol 3.94 g, 16.89 mmol DCM (B) 120 mL 100 ml 100 ml Triethylamine (C) 2.87 ml, 20.61 mmol 2.92 ml, 20.98 mmol 2.59 mL, 18.58 mmol Boc 2 O (D) 4.35 ml, 18.73 mmol 4.43 ml, 19.08 mmol 3.92 mL, 16.89 mmol
- reaction mixture cleared to a yellow solution and was stirred for 2 h.
- LCMS analysis showed product formation, however the SM peak was obscured by by-product so it was difficult to confirm reaction had gone to completion.
- the reaction was left to stir overnight (20 h).
- the reaction mixture was concentrated under vacuum.
- the residue was purified by silica chromotagraphy. The residue was loaded in DCM on a 340g silica cartridge and purified using a 0-40% EtOAc/cyclohexane gradient.
- the degree of reliability (the confidence limit) is assessed using the absolute values of two parameters: total neighborhood similarity for the VCD correlation (TNS (VCD)) and the enantiomeric similarity index (ESI).
- the degrees of reliability based on CompareVOA analysis are as follows: Reliability *TNS (VCD) (range) *ESI (range) Confidence Limit (CL) (range) High ⁇ 70 ⁇ 60 > 99% Medium 60-70 50-60 95 - 99% Low 50-60 40-50 90 - 95% Unreliable ⁇ 50 ⁇ 40 ⁇ 90% *absolute value
- the aqueous layer was washed with 10%MeOH/DCM (2 x 20 mL) and the combined organics dried (Na 2 SO 4 ) and concentrated in vacuo to afford a yellow oil which solidified on standing (44 mg). Due to the poor recovery it was assumed the remainder of the product remained in the aqueous layer.
- the aqueous layer was further extracted with EtOAc (20 mL), DCM (2 x 20 mL) and 10% MeOH/DCM (8 x 10 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated in vacuo.
- tert -Butyl ((3S,4R)-4-hydroxypiperidin-3-yl)carbamate (60.3 mg, 0.279 mmol) was added in DMF (1.5 mL) and the reaction stirred at RT for 16 h. LCMS showed complete reaction. Water (20 mL) and Et 2 O (20 mL) were added and the layers separated. The aqueous layer was extracted with further Et 2 O (2 x 20 mL) and the combined organics washed with water (2 x 20 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to afford a yellow oil.
- the aqueous layer was further extracted with diethyl ether (2 x 50 mL).
- the organic layers were collected, dried (Na 2 SO 4 ), passed through a hydrophobic frit and concentrated under vacuum to afford 330mg of crude product as an orange oil.
- the crude product was dissolved in a minimum volume of DCM and purified by column chromatography (25g silica). The column was eluted with a gradient of 60-100% ethyl acetate/cyclohexane.
- the reaction vessel was sealed and heated in Biotage Initiator microwave to 190 °C for 2 h. After allowing the reaction mixture to cool, LCMS showed ⁇ 37% conversion to the desired product, as well as ⁇ 12% conversion to the hydrolysed product.
- the reaction mixture was concentrated in vacuo to give the crude product, methyl 2-(1-ethyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole-5-carboxylate (512 mg, 1.224 mmol, 171 % yield) as a brown gum which was used without further purification.
- the crude product was loaded in DCM, onto a 50g SNAP Si-cartridge, purified by SP4, eluting with 0-5% methanol in DCM (15CV). The appropriate fractions were combined and the solvent was evaporated under vacuo to give an impure product.
- the BOC-protected product was taken up in dichloromethane (DCM) (5 ml) and treated with TFA (0.663 ml, 8.61 mmol).
- Example 8 2-(5- ⁇ [(3 R )-3-Amino-1-piperidinyl]carbonyl ⁇ -1-methyl-1H-benzimidazol-2-yl)-1-ethyl-1 H -pyrrolo[2,3- b ]pyridin-5-ol
- Example 10A (R)-(3-Aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone
- Example 10B (R)-(3-Aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzofdlimidazol-5-yl)methanone, hydrochloride
- Example 11A (R)-(3-Aminopiperidin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzofdlimidazol-5-yl)methanone
- Example 11B (R)-(3-Aminopiperidin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride
- Example 13 ((3 S ,4 R )-3-Amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride
- Example 14 ((3 S ,4 R )-3-Amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride
- Example 15 (R)-(3-Aminopiperidin-1-yl)(2-(1-ethyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazol-5-yl)methanone Prepared in a similar manner to Example 1 from (R)- tert -butyl (1-(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate.
- the oil was dissolved in methanol and loaded onto a SCX cartridge (10 g).
- the column was washed with MeOH (3CV) and the product collected as the free base with 2M ammonia in methanol (8CV).
- the product was concentrated in vacuo to afford a colourless oil.
- the product was dissolved in of 1:1 DMSO/MeOH (1.8 mL) and two 0.9 mL samples were purified by MDAP (Method E).
- Example 23 (( cis )-5-Amino-2-methylpiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (enantiomer of Example 24 with cis -relative stereochemistry)
- Example 24 (( cis )-5-Amino-2-methylpiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride
- Recombinant human PAD4 (residues 1-663) was expressed in E. coli as an N-terminal GST-tagged fusion protein. During purification of the protein, the GST tag was removed by cleavage with PreScission Protease (GE Healthcare). Activity of the final product was determined using a FLINT NH 3 release assay.
- reaction was initiated by the addition of 4 ⁇ l of substrate buffer containing 3mM N- ⁇ -benzoyl-L-arginine ethyl ester (BAEE), 100mM HEPES, 50mM NaCl, 600uM CaCl 2 (2H 2 O) and 2mM DTT, pH 8.0.
- substrate buffer containing 3mM N- ⁇ -benzoyl-L-arginine ethyl ester (BAEE), 100mM HEPES, 50mM NaCl, 600uM CaCl 2 (2H 2 O) and 2mM DTT, pH 8.0.
- the reaction was stopped after 100mins with the addition of 38 ⁇ l stop/detection buffer containing 50mM EDTA, 2.6mM phthalaldehyde and 2.6mM DTT.
- Assay incubated at room temperature for 90mins before measuring fluorescent signal ( ⁇ ex 413/ ⁇ em 476) on an Envision plate reader (Perkin Elmer Life Sciences, Waltham, MA, USA)
- PAD4 enzyme diluted to an assay concentration of 30nM in assay buffer (100mM HEPES, 50mM NaCl, 2mM DTT and 0.6mg/ml BSA pH 8), and added to wells containing 0.1 ⁇ l of various concentrations of compound or DMSO vehicle (0.8% final) in a Greiner high volume 384 well black plate. Following 30mins pre-incubation at room temperature, the reaction was initiated by the addition of 4 ⁇ l of substrate buffer containing 3mM N- ⁇ -benzoyl-L-arginine ethyl ester (BAEE), 100mM HEPES, 50mM NaCl, 600uM CaCl 2 (2H 2 O) and 2mM DTT, pH 8.0.
- assay buffer 100mM HEPES, 50mM NaCl, 600uM CaCl 2 (2H 2 O) and 2mM DTT, pH 8.0.
- Recombinant human PAD2 (residues 1-665) was expressed in baculovirus-infected Sf9 insect cells as an N-terminal 6His-FLAG-tagged fusion protein. Activity of the final product was determined using a FLINT NH 3 release assay.
- PAD2 enzyme diluted to an assay concentration of 30nM in assay buffer (100mM HEPES, 50mM NaCl, 2mM DTT, 7.5% glycerol and 1.5mM CHAPS pH 8), and added to wells containing 0.1 ⁇ l of various concentrations of compound or DMSO vehicle (0.8% final) in a Greiner high volume 384 well black plate.
- assay buffer 100mM HEPES, 50mM NaCl, 2mM DTT, 7.5% glycerol and 1.5mM CHAPS pH 8
- reaction was initiated by the addition of 4 ⁇ l of substrate buffer containing 180uM N-a-benzoyl-L-arginine ethyl ester (BAEE), 100mM HEPES, 50mM NaCl, 240uM CaCl 2 (2H 2 O) and 2mM DTT, pH 8.0.
- substrate buffer containing 180uM N-a-benzoyl-L-arginine ethyl ester (BAEE), 100mM HEPES, 50mM NaCl, 240uM CaCl 2 (2H 2 O) and 2mM DTT, pH 8.0.
- the reaction was stopped after 90mins with the addition of 38 ⁇ l stop/detection buffer containing 50mM EDTA, 2.6mM phthalaldehyde and 2.6mM DTT.
- Assay incubated at room temperature for 90mins before measuring fluorescent signal ( ⁇ ex 405/ ⁇ em 460) on an Envision plate reader (Perkin Elmer Life Sciences, Waltham, MA
- Examples 1, 2A, 2B, 3, 4A, 4B, 5B, 6, 7, 8, 9A, 9B, 10B, 11A, 11B, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 were tested in the PAD4 enzyme assay above or similar assays and had a mean pIC 50 in the range of 5 to 7.5.
- the mean pIC 50 for Example 5B was 6.7;
- Example 9B mean pIC 50 was 6.7;
- Example 11 B mean pIC 50 was 6.9; for Example 14, mean pIC 50 was 7.1.
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HUE12740581A HUE033294T2 (en) | 2012-07-26 | 2012-07-26 | 2- (azaindol-2-yl) benzimidazoles as PAD4 inhibitors |
SI201230769A SI2877467T1 (sl) | 2012-07-26 | 2012-07-26 | 2-(azaindol-2-il)benzimidazoli kot PAD4 inhibitorji |
PT127405819T PT2877467T (pt) | 2012-07-26 | 2012-07-26 | 2-(azaindol-2-il)benzimidazóis como inibidores de pad4 |
RS20170121A RS55684B1 (sr) | 2012-07-26 | 2012-07-26 | 2-(azaindol-2-il)benzimidazoli kao pad4 inhibitori |
HRP20161530TT HRP20161530T1 (hr) | 2012-07-26 | 2016-11-21 | 2-(azaindol-2-il)benzimidazoli kao pad4 inhibitori |
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PCT/EP2012/064649 WO2014015905A1 (en) | 2012-07-26 | 2012-07-26 | 2 - (azaindol- 2 -yl) benz imidazoles as pad4 inhibitors |
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Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3298003B1 (en) * | 2015-05-21 | 2023-04-19 | GlaxoSmithKline Intellectual Property Development Limited | Benzoimidazole derivatives as pad4 inhibitors |
AR107030A1 (es) * | 2015-12-09 | 2018-03-14 | Padlock Therapeutics Inc | Inhibidores aza-bencimidazol de pad4 |
AR107032A1 (es) * | 2015-12-09 | 2018-03-14 | Padlock Therapeutics Inc | Inhibidores bicíclicos de pad4 |
SG11201807021UA (en) | 2016-02-23 | 2018-09-27 | Padlock Therapeutics Inc | Heteroaryl inhibitors of pad4 |
CN107188867A (zh) * | 2016-03-14 | 2017-09-22 | 中国科学院天津工业生物技术研究所 | 精氨酸脱亚氨酶4的抑制剂 |
WO2018022897A1 (en) * | 2016-07-27 | 2018-02-01 | Padlock Therapeutics, Inc. | Covalent inhibitors of pad4 |
EP3510025B1 (en) * | 2016-09-12 | 2022-06-29 | Padlock Therapeutics, Inc. | Heteroaryl inhibitors of pad4 |
US11208386B2 (en) | 2016-12-02 | 2021-12-28 | University Of Massachusetts | Inhibitors of protein arginine deiminases (PADs) and methods of preparation and use thereof |
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BR112020005489A2 (pt) * | 2017-09-22 | 2020-09-24 | Jubilant Epipad Llc, | composto da fórmula (i), composto de fórmula (ii), composto de fórmula (iii), processo de preparação de compostos de fórmula (i), processo de preparação de compostos de fórmula (ii), processo de preparação de compostos de fórmula (iii), composição farmacêutica, método para inibir uma ou mais famílias pad em uma célula, método para tratar uma afeção mediada por um ou mais pads, utilização do composto, método para o tratamento e/ou prevenção de uma afeção mediada por um ou mais distúrbios da família pad, método para o tratamento de artrite reumatoide e método de tratamento de câncer |
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BR112020008851A2 (pt) | 2017-11-06 | 2020-10-20 | Jubilant Prodel LLC | composto da fórmula i, processo de preparação de compostos da fórmula i, composição farmacêutica, método para o tratamento e/ou prevenção de várias doenças, uso, método para o tratamento de câncer, método de tratamento de câncer e método para o tratamento e/ou prevenção de câncer e doenças infecciosas |
JP7368369B2 (ja) | 2017-11-24 | 2023-10-24 | ジュビラント・エピスクライブ・エルエルシー | Prmt5阻害剤としてのヘテロ環式化合物 |
WO2019161803A1 (zh) * | 2018-02-26 | 2019-08-29 | 南京药捷安康生物科技有限公司 | 肽酰精氨酸脱亚胺酶抑制剂及其用途 |
WO2019175897A1 (en) | 2018-03-13 | 2019-09-19 | Jubilant Biosys Limited | Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation |
KR20210042932A (ko) * | 2018-08-08 | 2021-04-20 | 브리스톨-마이어스 스큅 컴퍼니 | Pad4 억제제로서의 치환된 벤즈이미다졸 |
WO2020033514A1 (en) * | 2018-08-08 | 2020-02-13 | Bristol-Myers Squibb Company | Benzimidazole inhibitors of pad enzymes |
JP2021534108A (ja) * | 2018-08-08 | 2021-12-09 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Pad酵素のインドールおよびアザインドール阻害剤 |
CN112566916B (zh) | 2018-08-08 | 2023-10-20 | 百时美施贵宝公司 | 作为pad4抑制剂的经取代的噻吩并吡咯 |
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EP3994128A4 (en) * | 2019-07-03 | 2022-12-07 | University of Massachusetts | PROTEIN ARGININE DEIMINASE (PAD) INHIBITORS AND METHODS OF PREPARATION AND USE THEREOF |
TW202115083A (zh) * | 2019-09-27 | 2021-04-16 | 大陸商南京藥捷安康生物科技有限公司 | 肽醯精胺酸脫亞胺酶抑制劑及其用途 |
KR20220137694A (ko) * | 2020-02-06 | 2022-10-12 | 브리스톨-마이어스 스큅 컴퍼니 | 면역억제제로서 유용한 마크로시클릭 pad4 억제제 |
TW202140477A (zh) * | 2020-02-12 | 2021-11-01 | 美商必治妥美雅史谷比公司 | 雜環pad4抑制劑 |
CN111265526B (zh) * | 2020-04-09 | 2021-03-19 | 黑龙江中医药大学 | 一种治疗胃癌的药物及其制备方法 |
CR20220550A (es) * | 2020-04-30 | 2022-12-15 | Gilead Sciences Inc | Inhibidores macrocíclicos de las peptidilarginina deiminasas |
KR20230093251A (ko) | 2020-09-10 | 2023-06-27 | 프리시릭스 엔.브이. | Fap에 대한 항체 단편 |
WO2022059779A1 (ja) | 2020-09-18 | 2022-03-24 | 大日本住友製薬株式会社 | アミン誘導体 |
US11878965B2 (en) | 2020-12-22 | 2024-01-23 | Gilead Sciences, Inc. | Inhibitors of peptidylarginine deiminases |
EP4433477A1 (en) | 2021-11-15 | 2024-09-25 | Regor Pharmaceuticals, Inc. | Pad4 inhibitors and use thereof |
WO2023203135A1 (en) | 2022-04-22 | 2023-10-26 | Precirix N.V. | Improved radiolabelled antibody |
WO2023213801A1 (en) | 2022-05-02 | 2023-11-09 | Precirix N.V. | Pre-targeting |
WO2023230609A1 (en) * | 2022-05-26 | 2023-11-30 | Celgene Corporation | Heterocyclic pad4 inhibitors |
WO2024109945A1 (en) * | 2022-11-24 | 2024-05-30 | Helios Huaming Biopharma Co., Ltd. | Selenium containing heterocycle compounds and use thereof |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU570439B2 (en) | 1983-03-28 | 1988-03-17 | Compression Labs, Inc. | A combined intraframe and interframe transform coding system |
SI0820279T1 (en) | 1995-04-14 | 2002-12-31 | Smithkline Beecham Corporation | Metered dose inhaler for albuterol |
TW533865U (en) | 1997-06-10 | 2003-05-21 | Glaxo Group Ltd | Dispenser for dispensing medicament and actuation indicating device |
EP1114052B1 (en) * | 1998-09-18 | 2005-11-16 | Abbott GmbH & Co. KG | 4-aminopyrrolopyrimidines as kinase inhibitors |
US6315112B1 (en) | 1998-12-18 | 2001-11-13 | Smithkline Beecham Corporation | Method and package for storing a pressurized container containing a drug |
US6390291B1 (en) | 1998-12-18 | 2002-05-21 | Smithkline Beecham Corporation | Method and package for storing a pressurized container containing a drug |
US6119853A (en) | 1998-12-18 | 2000-09-19 | Glaxo Wellcome Inc. | Method and package for storing a pressurized container containing a drug |
US6352152B1 (en) | 1998-12-18 | 2002-03-05 | Smithkline Beecham Corporation | Method and package for storing a pressurized container containing a drug |
ATE290865T1 (de) | 1999-10-19 | 2005-04-15 | Merck & Co Inc | Tyrosin kinase inhibitoren |
CA2699568C (en) | 1999-12-24 | 2013-03-12 | Aventis Pharma Limited | Azaindoles |
GB0115393D0 (en) | 2001-06-23 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
WO2003000690A1 (en) | 2001-06-25 | 2003-01-03 | Aventis Pharmaceuticals Inc. | Synthesis of heterocyclic compounds employing microwave technology |
CN1901958B (zh) | 2003-11-03 | 2011-03-09 | 葛兰素集团有限公司 | 流体分配装置 |
CA2546192C (en) | 2003-11-17 | 2010-04-06 | Pfizer Products Inc. | Pyrrolopyrimidine compounds useful in treatment of cancer |
FR2862971B1 (fr) * | 2003-11-28 | 2006-03-24 | Sod Conseils Rech Applic | Nouveaux derives de benzimidazole et d'imidazo-pyridine et leur utilisation en tant que medicament |
US7429611B2 (en) | 2004-09-23 | 2008-09-30 | Bristol-Myers Squibb Company | Indole inhibitors of 15-lipoxygenase |
EP2205085A1 (en) * | 2007-09-25 | 2010-07-14 | Merck Sharp & Dohme Corp. | 2-aryl or heteroaryl indole derivatives |
JP2011521961A (ja) | 2008-05-28 | 2011-07-28 | ワイス・エルエルシー | 3−置換−1H−インドール化合物、mTORキナーゼおよびPI3キナーゼ阻害剤としてのそれらの使用、ならびにそれらの合成 |
RU2011106786A (ru) * | 2008-07-23 | 2012-08-27 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | Ингибиторы пиразолопиридинкиназы |
EP2414328B1 (en) * | 2009-04-02 | 2021-05-26 | Merck Serono S.A. | Dihydroorotate dehydrogenase inhibitors |
US20100305093A1 (en) | 2009-04-09 | 2010-12-02 | Exelixis, Inc. | Inhibitors of mTOR and Methods of Making and Using |
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